Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniae

Abstract

Chitinases and chitinase-like proteins are an evolutionary conserved group of proteins. In the absence of chitin synthesis in mammals, the conserved presence of chitinases suggests their roles in physiology and immunity, but experimental evidence to prove these roles is scarce. Chitotriosidase (chit1) is one of the two true chitinases present in mammals and the most prevalent chitinase in humans. In this study, we investigated the regulation and the role of chit1 in a mouse model of lung infection. We show that chitinase activity in bronchoalveolar lavage fluid is significantly reduced during lung infection. This reduced activity is inversely correlated with the number of neutrophils. Further, instilling neutrophil lysates in lungs decreased chitinase activity. We observed degradation of chit1 by neutrophil proteases. In a mouse model, chit1 deficiency provided a significant advantage to the host during lung infection by limiting bacterial dissemination. This phenotype was independent of inflammatory changes in chit1 mice as they exerted a similar inflammatory response. The decreased dissemination resulted in improved survival in chit1 mice infected with in the presence or absence of antibiotic therapy. The beneficial effects of chit1 deficiency were associated with altered Akt activation in the lungs. Chit1 mice induced a more robust Akt activation postinfection. The role of the Akt pathway in lung infection was confirmed by using an Akt inhibitor, which impaired health and survival. These data suggest a detrimental role of chit1 in lung infections.

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

“…Previous studies have documented that CD14 deficiency was associated with altered kinetics of P. aeruginosa ‐induced keratitis, implicating CD14‐triggered pathways in promoting inflammation‐induced corneal tissue damage in the C57BL/6 mice . Consistently, Chit1 deficiency altered inflammatory responses to K. pneumoniae in the infected lungs of C57BL6 mice, resulting in less pathology . Last, overexpression of cathepsin E was associated with alterations in the kinetics of phagolysosomal assembly, terminating phagolysosomal maturation .…”

“…49 Consistently, Chit1 deficiency altered inflammatory responses to K. pneumoniae in the infected lungs of C57BL6 mice, resulting in less pathology. 50 Last, overexpression of cathepsin E was associated with alterations in the kinetics of phagolysosomal assembly, terminating phagolysosomal maturation. 51 Cumulatively, these data illustrate that the infected SW-derived PMNs had proteomes that bear unique features, reflective of distinct neutrophil functions that were associated with improved recovery.…”

Mechanisms of Epithelial Immunity Evasion by Respiratory Bacterial Pathogens

“…As inflammation is essential for effective clearance of invading bacterial pathogens, the pathogens can evade this inflammation by either suppressing the inflammatory response or by causing excessive inflammatory response. K. pneumoniae lung infections often induce very limited early inflammatory response, and it successfully disseminates across organs before inducing a robust inflammatory response (59). Klebsiella inhibits the activation of NFkB and MAPK pathway by promoting the expression of ubiquitinating enzyme CYLD in lung epithelial cells (60).…”

Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

“…2B). Chitotriosidase is a hydrolase produced by alveolar macrophages in response to infection (30)(31)(32) and its expression has been associated with both granulomatous and fibrotic lung diseases (33). Indeed, serum CHIT1 has been investigated as a biomarker of disease severity and progression in several lung diseases, including chronic obstructive pulmonary disease (34).…”